There’s a familiar rhythm to the most prominent autism gene hunt publications. Their authors hype their newly minted study aggressively in the media. The prestigious journals that publish them lend their imprimatur to press releases that say, “this study is a big deal.” The findings sound impressive in the press release (and the authors get plenty of time on camera and in leading newspapers to tell us how truly impressive they are). In the meantime--in papers that are so densely written that making sense of what they really say requires far more reflection than the media hype cycle permits--skillfully concealed evidence reveals the truly important news in the findings: the authors whisper quietly (if at all) that the new analysis negates the most important findings of some of the most prominent previous gene hunts, while crucial detail on their new findings is often relegated to “supplementary material” that’s not available on the publication date.

All of these patterns will almost certainly be on display today as the latest missive from the autism-genetics establishment bursts forth in the form of not just one, but two major papers in the journal Nature. But I warn you, don’t be fooled by the hype. These two studies report a few moderately interesting findings, which isn’t a bad thing. Broadly speaking, trustworthy and actionable biological findings about autism are something all autism parents should welcome, whether they’re about genes or the environment or the interaction between the two. And indeed, most autism parents I know generally agree that there OUGHT to be some kind of genetic susceptibility that we can discover in autism.

But what’s truly remarkable in these two papers is how so much will be made about so very little.--That said, the publication of these two papers--one on the risk of rare mutations (copy number variants) in “autism genes”, the other on common inherited genes (reported here in the form of “single nucleotide polymorphisms” or SNPs) that may increase autism risk--creates an opportunity to review the current state of the great autism gene hunt, something I’ve wanted to do for a while. I’ll break the review into four pieces

1. What you should know about the lead authors and their funding2. What the paper on “copy number variants” really says3. Why the paper on common genetic variations will get the most hype4. How to distinguish faith from reality in reading the results

1. The Lead Authors and their Motives

For the autism parent community, the biggest news in this PR blitz is not the work itself, but rather who stands behind it. The work is billed as a collaboration between the Autism Genetic Resource Exchange (AGRE) group from Autism Speaks and the Center of Applied Genomics at the Children’s Hospital of Philadelphia (CHOP).

That’s right. CHOP.

Autism Speaks’ AGRE program is right at the center of most American autism gene research so it’s not surprising to see them involved, but the interesting part in these two prominent studies is that Autism Speaks has clearly taken a back seat to CHOP in controlling this project. Researchers from CHOP spearheaded the study design and report writing. CHOP appears to have funded a material potion of the work on their own. And the corresponding author on both papers, Hakon Hakonarson, is the Director of CHOP’s Center for Applied Genomics (CAG).

With CAG and CHOP at the center of this research, it’s certainly reasonable to ask, what connection does this work have to Paul Offit? Especially in light of the $182 million that CHOP received last year from selling its rights to the Merck rotavirus vaccine, is the Merck vaccine not only making Paul Offit a wealthy man, but also financing his personal crusade to exonerate the environment in general (and vaccines in particular) from any role in causing autism?

As we reported previously (HERE) Offit and CHOP have declined comment on the distribution of the millions they received from the Merck vaccine, but one can get a few clues from CHOP’s official policy document on the distribution of patent royalty income (HERE): 30% goes to the inventor(s) (in this case Offit alone), 25% to the inventor’s lab and department and the remaining 45% to the general CHOP research budget.

It’s impossible to know where all that Merck money is going if CHOP won’t disclose it, but it’s reasonable to speculate. Could the lion’s share of these millions really be going to the Infectious Disease Section where Offit officially hangs his hat? That would be hard to imagine: if you visit the web-site (HERE) you will find that there’s really not much going on in infectious disease. As a research area, it’s certainly not particularly sexy. One clue to the patent royalty distribution might come from Offit’s other recent choice: when he was demonstrating his compassion for families affected by autism, Offit made a big show of donating his book royalties to CHOP’s Center for Autism Research (CAR). Is there a connection between CAG and CAR? Yes there is and it’s Dr. Hakonarson himself: The corresponding author on the two new autism-gene papers is not only the Director of CAG, he is also a researcher at the CAR at CHOP (HERE).

Follow the acronyms. Merck to CHOP to CAR and CAG. Any way you slice it, there’s a pretty direct path from Merck’s vaccine profits to Hakonarson’s gene study with Paul Offit in the middle. None of which should negate the evidence any gene study produces, but it should certainly influence anyone who wants to calibrate the PR blitz we’re about to see.

2. The New Church of the Immaculate Mutation

The least radical of the two papers, “Autism genome-wide copy number variation reveals ubiquitin and neuronal genes”, is actually the most interesting from an autism research perspective. CNVs have recently become a hot topic in autism genetic research. Most notably, researchers from the Cold Spring Harbor (NY) Laboratory (2007) and the Boston-based Autism Consortium (2008) recently published papers, in Science and the New England Journal of Medicine, respectively, arguing that de novo copy number variants could provide genetic answers where all the research on inherited genes could not. Their theory was essentially one of mutation: the idea that the defects in the DNA of autistic children that caused the disorder were not present in their parents’ DNA but rather the result of newly created (or de novo) variations in the egg or sperm that subsequently combined to create the child.

The de novo CNV theory looked promising: most previous autism gene research had assumed that “autism genes” had to come from the parents and be passed on; studies therefore used analytical techniques that looked at linkage, i.e., the transmission of genes from parent to child. They consistently found little. The idea that the defects could be de novo opened up an entirely new field of possibilities.

One part of the idea made a great deal of sense. De novo variation is consistent with an environmental theory. One doesn’t need to dismiss the tenfold increase in autism rates to argue for genetic causation. Instead, one could argue that the autism epidemic has resulted from all kinds of environmental toxins that were wrecking havoc on the reproductive fitness of modern parents, basically leading to widespread mutations in eggs and sperm. The corollary was that the relevant environmental injury had nothing to do with what happened to the embryo itself, not to mention the infant. All the damage took place before conception, occurred in sperm and egg cells, and of course had nothing to do with vaccines.

But if the de novo CNV theory was plausible at one level, it was absurd at another. The genetic mutations the theory proposed (because this was the best the available evidence could support) were completely non-specific. The copy variants were spread widely (even randomly) over the genome, the theory went. No individual mutation was responsible for autism, just the unhappy presence of the wrong one. And these non-specific mutations were not only widely spread, they were virtually undetectable in the infant: no dysmorphic features; generally normal birth and (in many cases development); and the beautiful children we so often see affected by autism.

In other words these CNVs were a case of immaculate mutations.

And it was the perfect new project for the genetics research community. A wide open field of research opportunities. Lots of new money. And a chance to explain past failure away as part of the inexorable march towards genetic understanding.

Unfortunately, the religious zeal with which the genetics field took on CNVs began to run into difficulty as the evidence didn’t cooperate very well with the theory. The Cold Spring Harbor paper found de novo CNVs in 14 out of 195 autism cases as compared to 2 out of 196 controls. These were scattered around chromosomes 2, 3, 6, 7, 13, 15, 16, 20 and 22. But only a few of these were in regions that had ever been raised before in autism gene research. More to the point, the researchers had very little idea what common pathway might be involved in this seemingly random selection of individual mutations. The mutations--though more common in the autism genomes, they claimed--were limited in number, not really the outcome of a “fragile-genome disorder.” Most of them didn’t go along with any known genes. They confessed that “these studies do not address the mechanisms by which structural mutations of genes contribute to autism.”

And then, like the heritability studies that went before, the studies started contradicting each other. The Autism Consortium study published in the NEJM, waited until the penultimate paragraph before conceding that “a comparison of our findings with those of other recent studies that have reported de novo copy-number variations in autism does not add evidence in favor of susceptibility to autism conferred by other recently highlighted genomic regions.”

There was one major exception, however, and that was a region on chromosome 16 (16p11.2 to be precise) that received all the focus of the gene hunt PR machinery. “A hot spot of genetic instability in autism”, was discovered on 16p11.2, proclaimed an accompanying NEJM editorial that also advertised the attractions of the new theory. “These examples highlight a different paradigm for the genetic basis of autism. Rather than being an inherited disease, autism may be the result of many independent loci that rarely delete or duplicate during gamete [sperm or egg] production.”

Publishing these findings in the prestigious New England Journal of Medicine required the authors to meet some unusually high standards. More so than the Cold Spring Harbor paper, the 16p11.2 finding was made with modesty in its claims. In the original sample of 751 families (genes provided again by AGRE), only four (barely half a percent) showed the most durable CNV result, a deletion of DNA on 16p11.2. Normally, this trivial a result wouldn’t merit publication in a journal like NEJM. But the difference here was that the Autism Consortium could claim that they had replicated the specific CNV finding, not once but twice, in two different samples. There would be more details to come in the supplementary material, but the fact that three entirely unrelated samples (the AGRE original and then separate replications from Boston Children’s Hospital and from Iceland) had shown the same result, <1% deletion in “cases” and close to 0% in controls, was a landmark finding.

I spoke to one of the Autism Consortium researchers at the time (she was trying to recruit our family to donate samples). They were very pleased with themselves that they had “explained” half a percent of the cause of autism.

And then along comes today’s CHOP CNV publication. It’s good news for them (word is they’re pleased with themselves too). Like the NEJM paper, the CHOP paper claimed to have replicated their findings in two separate samples: the AGRE and the CHOP cohorts. Unfortunately for the Autism Consortium, the news for replication of the “hot spot” on 16p11.2 was not so good. “We observed a similar frequency of deletions and duplications of the 16p11.2 locus in the ASD cases (~0.3%) as previously reported; however the CNV frequency in the control subjects at this locus was also comparable to that of the cases.”

So much for the hot spot.

But the CHOP CNV paper also departs from the Boston and NY papers in a different and more important way. They report their own set of “enriched” areas of CNVs. But unlike the other papers that reported de novo variations, the CHOP CNVs were almost entirely inherited (in fact, they reported surprisingly low levels of de novo variation). With that finding, not only did the 16p11.2 hot spot go down the drain, so did the “new paradigm for the genetic basis of disease.”

So much for an environmentally-based theory of genetic causation.

And so it goes. What we’re seeing now won’t be reported widely, but it’s an important silent finding. Effectively, the New Church of the Immaculate Mutation is stumbling from enthusiasm into a new crisis of faith. And the news gets worse, because not only did some landmark findings fail their first major replication test, but in the retrospective analysis they’re going to find themselves vulnerable to critical flaws in their previously acclaimed analysis of de novo CNVs. Here’s a few that I’ve found interesting.

• The 16 p11.2 “hot spot” was developed based on an original finding of both deletions and duplications. The duplication CNV wasn’t found in the Iceland group and was questionable in the Boston Children’s Hospital group

• The second sample from Boston Children’s Hospital was made up of “case subjects that had received the diagnosis of developmental delay, mental retardation or autism spectrum disorder.” That’s right, it said “OR autism spectrum disorder.” The second replication sample wasn’t really an autistic sample at all, a limitation that should place a serious cloud on their second claim to replication for the CNVs they found in the initial group.

• In fact, in reviewing the “supplementary material”, the (scantily) reported history of the “autistic” cases makes one highly suspicious that these are really cases of autism at all. There is no clear diagnosis listed and several symptom areas that would be markers of autism were reported in which the entry was merely “NA.”

So it appears the much hyped replications were far less robust than the study authors claimed and perhaps the CHOP study has now revealed the weakness in the Autism Consortium’s methods.

But even in the CHOP study, it’s not clear that the latest set of CNVs is any more reliable than the Autism Consortium’s. The CHOP study took a full genome scan of both the AGRE and CHOP samples and reported on the handful that showed up “significant” (meaning they had low P values) in both. Notably, the paper itself doesn’t describe the overall results as “significant”, but rather “positive” and “enriched.” That’s because the standard for separating meaningful results from noise in a full genome scan is higher than a typical analysis: there is so much data in the full genome that one would expect low P values in a random analysis.

For all these reasons (it rejects the 16p11.2 “hot spot”; it failed to find de novo variation; it doesn’t meet a high standard of statistical validity) that’s why the CHOP CNV paper is getting far less attention than the more traditional study: a straightforward sequel to past analysis of inherited genes. Let’s turn to that one now.

3. The Orthodox Church of the Common Variant

In order to understand the importance of the second Nature article, you need to understand a critical bit of background about a raging debate among geneticists right now. There has been a crisis brewing for a while among the genetic research faithful. The New York Times reported on this crisis in a September 16th, 2008 article. In the opening paragraph, the reporter summarized the large stakes involved.

“The principal rationale for the $3 billion spent to decode the human genome was that it would enable the discovery of the variant genes that predispose people to common diseases like cancer and Alzheimer’s. A major expectation was that these variants had not been eliminated by natural selection because they harm people only later in life after their reproductive years are over, and hence that they would be common. This idea, called the common disease/common variant hypothesis, drove major developments in biology over the last five years. “

But after many years of investigation, the search for common variant has been widely judged a failure. And that failure has precipitated a remarkable crisis of faith among geneticists. The New York Times article quoted David B. Goldstein of Duke University, a population geneticist who basically said to the faithful that God was dead. “It’s an astounding thing,” Dr. Goldstein said, “that we have cracked open the human genome and can look at the entire complement of common genetic variants, and what do we find? Almost nothing. That is absolutely beyond belief.” That wasn’t good news for the practical application of genomics, said Goldstein. “There is absolutely no question,” he said, “that for the whole hope of personalized medicine, the news has been just about as bleak as it could be.”

Most of you probably missed a recent series on genetic analysis of disease in the April 23rd issue of the New England Journal of Medicine. Goldstein and several other authors contributed editorial commentaries, all of which focused on the implications of the newly recognized limits of common variant analysis in deciphering human disease. They each tried to find the silver lining in the failure. Goldstein argued to search for rare variants rather than common ones. Peter Kraft and David Hunter of Harvard argued doctors could save time and money, claiming that “the positive predictive value of a genetic test [for human disease] will almost always be low.” Joel Hirschhorn of MIT tried to cheer the faithful up with the argument that genetic analysis was not really about genes after all. “The success of genomewide studies is not tied to prediction”, argued Hirschhorn. “If we identify only new pathways underlying disease, these studies will have a tremendous impact.”

In the midst of this crisis of the orthodox faith in the grand human genome project, the big news in the CHOP autism papers becomes more evident, especially the second one, “Common genetic variants on 5p14.1 associate with autism spectrum disorder.” Here is where the real focus of the press release just issued by Nature has been placed.

“The first robust evidence of common genetic variation having a role in autism is presented online in Nature this week. The research pinpoints significant single-nucleotide polymorphisms (SNPs) that appear to have a strong genetic association with autism, and marks the first identification of this kind for the disease. The discovery of these SNPs suggests that, in contrast to what was previously thought, common genetic variation can contribute to autism spectrum disorders (ASDs).”

The search for common gene variants in autism requires another kind of technique, not a mutation search but a linkage analysis. There have been millions of dollars spent on linkage studies in autism, by over 10 different groups carrying out even more individual genome scans.

(I reviewed these studies HERE) The bottom line: like so much of the genetic analysis in autism, none of these studies can sustain a reproducible result. Why? Since the genome is so large, these linkage studies are like massive random number generators: any individual study will find a significant finding somewhere in the genome all of which end up being false signals of disease risk. This law of large numbers was famously demonstrated by leading geneticists Eric Lander and Leonid Kruglyak in a simulation model.

“To illustrate the random fluctuations expected in a whole genome scan, we generated simulated genotypes assuming independent assortment throughout the genome—that is that there are no trait causing loci. All positive scores in such data necessarily represent random fluctuations, not true linkage…[In the simulation, a] single region on chromosome 14 reached the status of suggestive linkage, as expected, while no region showed significant linkage. If these results had occurred in a real dataset, an investigator would likely call attention to the possibility of linked genes on chromosome 14…The example thus illustrates that false positives can cluster in candidate regions and otherwise mimic true loci.”

In scan after autism scan, researchers have fallen into this trap. Some region shows up with a significant result, the authors hope against hope (they’ve all read Lander and Kruklyak) that their “suggestive” finding is really a true risk factor, the next wave of studies comes out and lo and behold the old suggested regions are rejected and new “suggestive” (and sometimes even “significant”) findings emerge. This has gone on so frequently, it’s become a real embarrassment to the genetic community.

So what’s different about this Nature paper? After all, Nature sets higher standards, right? Well judge for yourself. Remember, for the linkage study, the authors were using two data samples, one from Autism Speaks (AGRE) and one from CHOP (ACC). When they did their linkage analysis, here’s what Hakonarson and colleagues report.

• “We did not observe genome-wide significant association (P < 5 X 10-8 ) to ASDs in the AGRE cohort, but we proposed that meaningful associations were contained within the lowest P values.”

• “Therefore we subsequently performed a combined analysis of these two independent data sets using recommended meta-analysis approaches…[and] one SNP located on 5p14.1 reached genome-wide significance…and five further SNPs at the same locus had P values below 1 X 10-4.”

If they had stopped after that, there would be no Nature article, since other research groups, most recently the Autism Genome Project Consortium (AGPC), have pooled similarly large samples and claimed the large sample revealed significant findings too (Lander and Kruglyak point out that if you run enough genome scans, the random number generator will generate a “significant” finding about 10% of the time). The AGPC study, published in 2007 with only a slightly smaller sample, reported a “significant” finding on chromosome 11p.11-12. Not surprisingly, however, the CHOP study doesn’t call attention to that previous effort. Also not surprising is the fact that the CHOP region of interest, 5p14.1, didn’t come up as significant at all in the AGPC analysis.

So if we’re just watching competing random number generators at work, why did Nature publish this new study? Because the CHOP group reported not one, but two additional replications of the initial significant finding.

• “To replicate our genome-wide significant association signals at the 5p14.1 locus, we examined the association statistics for these markers in a third independently generated and analyzed cohort…the association signals for all the aforementioned SNPs were replicated in this cohort with the same direction of association with P values ranging from 0.01 to 2.8 X 10-5.”

• “To seek further evidence of replication, we examined association statistics from a fourth independent cohort…[and] most of the SNPs were replicated (P < 0.05)…with the same direction of association.

So that’s the deal. Never mind the fact that this is a completely new area, never reported by ANY previous genome scan, or that the largest alternative study the AGPC found nothing there, or that the “replication” P values were relaxed relative to the “discovery” P values. But give the group some credit for jumping over a hurdle that others have struggled to clear.

Only time will tell whether this new “common genetic variant” falls by the wayside as other purported autism genes have before. For now, let’s accept the idea that the CHOP group found something of interest.

Accepting that as a premise, the first question you might ask is simple: So what’s the gene? Well there’s not exactly a gene at the 5p14.1 “allele.” The significant region is not on a known part of any gene. Rather, it’s in between two genes, specifically the region between two genes previously unexplored in autism known as cadherin 9 and cadherin 10.

The next question you might ask is more practical: so what do the two genes (that we’re not quite looking at but simply looking between) do? Well here’s where the CHOP group gets excited, because the cadherin 10 gene (tests on #9 were “uninformative") shows up in a test of fetal brain tissue. And more to the point, it looks like it could even be a brain development gene. “The cadherins represent a large group of transmembrane proteins that are involved in cell adhesion and the generation of synaptic complexity in the developing brain.” Okay, so maybe there’s something there, but it’s hard to know exactly what.

But the most important question might slip right past you: indeed it took me several readings to figure this out. The crucial question is this: how important is this “common variant”? The importance ought to be high if we’re going to get excited. Interestingly, the CHOP authors don’t feature the answer to this question, they place their measure of “MAF” (for “minor allele frequency”) in acronym form right next to their more featured P value findings. But the results are straightforward to interpret if you read the fine print and do some simple arithmetic. The essence of the answer is this: normal children had the common variant 61% (1 - 0.39, the MAF) of the time, while the autistic children had the common variant 65% of the time.

That’s it. 65% vs 61%. Do the math. Even if CHOP is right and these results hold up, we’re talking about less than a 10% difference. That’s all.

As Kraft and Hunter pointed out in their NEJM essay, “a striking fact about these first findings is that they collectively explain only a very small proportion of the underlying genetic contribution to most studied diseases.” How small is small for them? “The great majority of the newly identified risk marker alleles confer very small relative risks, ranging from 1.1 to 1.5.”

So the CHOP finding, if it’s not a statistical fluke, is at the low end of the range for risk prediction.

So much for common variants in autism

4. Moving Beyond Faith to Real Biological Insight

A closer reading of the recent autism genetic literature reveals a kind of strategic retreat under way among geneticists. Rather than focusing on individual genes or gene regions, most authors are beginning to follow Joel Hirschhorn’s advice and focus on extracting insights from the long list of genes that have emerged as promising, if eventually failed, candidates for strong autism causation. The insight, these scientists argue, might not lie in the specific gene but rather in the specific biological processes in which a larger number of genes cluster. There’s a certain wisdom in that. I know that in my reading of the autism gene literature, these weak signals are the findings I store away personally.

One source I know has argued that what’s interesting in all these findings is that the relevant genes “cluster around the synapse.” That’s clearly what the CHOP authors argue and it’s certainly possible.

But it’s also possibly wishful thinking. There are lots of genes that get bandied about in autism gene papers, and some of them are active in the nervous system. They even have names (neurexins and neuroligins) that make them sound like they’re “brain genes.” And since the orthodox view of autism requires that the disorder is clearly genetic and placed neatly within the brain, it’s not at all surprising that these scientists would be inclined to that interpretation.

But there are also any number of alternative clustering hypotheses. Ubiquitin, one of the genes involved in the CNV paper, is important for glutathione metabolism and could affect detoxification capacity. The supposedly “neuronal” genes show up all over the body, the neuroligins and neurexins are expressed in the gut and kidneys too. The cadherins keep cells together and one scientist I know points out that “Individuals with comparatively weak physical connectivity between neurons will be most vulnerable to environmental factors.” The cadherins are also involved in maintaining the blood brain barrier, another vector by which genes and environment could interact to injure susceptible children.

In short, who’s to say that these findings “cluster around the synapse” or for that matter exclusively affect the brain? There are as many interpretations of these findings as there are biases. The frustrating thing is that, in the aggregate, the findings don’t cluster very much. And as for any near term benefit for today’s autism families and children, the key point is this:

a) the chances are overwhelming (over 99%) that any of these mutations (inherited or de novo) don’t really affect your child, and

b) there’s very little chance that there’s much treatment insight coming any time soon in any common variant risk that might result from further study of the DNA between the cadherins.

In the end, we’ll all need to accept the coming hoopla on this study as yet another fleeting flail of a failing disease model, a “big hungry lie” that needs new studies to stay alive. It’s not surprising to see CHOP in the middle of it all, nor is it at all surprising to see larger doctrinal debates in scientific research playing themselves out with our children as guinea pigs. It’s just a shame to see all this money and attention placed on such flimsy foundations. There are so many more productive ways to spend that money and so little time for the children.

Sorry folks, but Autism is definitely inherited (I have an ASD, dx Asperger's and ADHD). Twin studies (and yes I'm a twin too though my non-identical twin sister doesn't have autism) look at identical (where they find an 80-90% chance that if one twin has autism the other will too) versus non-identical twins (30% chance of concordance). This is true even after correcting for the fact that identicals must be same sex (which will distort the figures because autism is more common in boys).

On the other hand , siblings of autistics have only about a 5% chance of it, suggesting something happening in utero can cause autism in those who have the wrong genes(like the mother having an illness while pregnant). But the 5% also suggests genetic origins, since the figure is only 1% or less in the general population.

What seems VERY unlikely is that both twins among the identicals were vaccinated but that the parents of the non-identicals decided to only have one twin vaccinated, who then becomes autistic. Certainly untrue in my own case. Ha!

CD wrote:
I do believe that there is some genetic susceptibility, but ONLY a susceptibility.
Identical versus fraternal twin studies have shown that if one twin has autism, the other twin has a higher chance of having autism also. This risk is higher in identical twins than fraternal (which suggests a genetic susceptibility), BUT the rate of both identical twins having autism is not 100% (which proves that autism must also have an environmental component).”

Examples of identical and fraternal twins lid to conclusion that somehow some children are more prone to be affected with autism.
But if we take closer look on autism prevalence among identical and fraternal twins it will be clear that there is no genetic susceptibility.
Actually, autism incidence and prevalence among identical and fraternal twins giving strong argument against genetic susceptibility

Prevalence of autism among identical twins is 12 times higher than among general population.
Compared to the general population, each twin alone is 12 times more prone to be affected with autism.

Because each twin alone is 12 times more likely to be affected with autism compared to general population it is clear why if one twin is affected with autism than other has higher chance of having autism too.

If one of identical twins is affected with autism the possibility that another twin is affected is higher than by fraternal twins and typical siblings.

In case of identical twins – if one twin has autism than another twin has 3 times more chance of having autism too compared to fraternal twins and 12 times more chance of having autism compared to typical siblings.

Another fact is that autism prevalence for fraternal twins is four times the rate for the general population.

While Identical twins share 100% genetic material fraternal twins share on average half of their genes, just like typical siblings.

Despite fact that fraternal twins and typical siblings share half of their gene, fraternal twins are fore times more likely to be affected with autism compared to typical siblings. The fact that fraternal twins are for times more likely to be affected with autism is a strong argument against genetically susceptibility

If one fraternal sibling is affected with autism, other fraternal sibling has four times more chance of having autism too compared to typical sibling, not because of genetic susceptibility but because it is not known why twins are more vulnerable to autism.

The question why identical twins are more prone to autism is reasonable starting point that s will lead to soling the problem of autism by twins, typical siblings and the rest of population.

But if starting point is genetic susceptibility then we are in the road to nowhere.

There are tons of studies on genes in schizophrenia. And almost as many studies pointing to involvement of prenatal infections in schizophrenia.

This paper sums up the issue beautifully:

Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease.http://schizophreniabulletin.oxfordjournals.org/cgi/content/abstract/sbn054v1

This comment is highly relevant to autism imo, as countless things point to involvement of early infections. As the author of the above paper put it so nicely "the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen..." (or toxin for that matter?).

For example if REST/NRSF gene involvement is found in autism (only my hypothesis at this point, no one has looked yet), this will probably be flagged as proof that autism is genetic.

BUT this gene/mechanism also is the main controller of viral expression in the nervous system - once say herpesvirus establishes itself in host CNS cells, or cells that make up the blood brain barrier, and goes into latent phase. Put simply this gene then ensures that this sleeping virus does not interfere with proper functioning of those cells.

Exactly the type of genetic/environmental research that should be carried out in schizophrenia. And autism.

This isn't the only reason that the MMR is a dangerous vax in this regard. The measles virus of the vax is cultured on chick embryo cells. These can be contaminated with MBP - myelin basic protein. The body, in mounting an immune reaction to the vax, would thus run an autoimmune reaction to its own MBP as well. (This possibility has been observed in a number of studies, particularly by V.K. Singh et al, with antibodies to MBP found in conjunction with the MMR measles virus in the damaged guts of children with autism.) There goes the blood brain barrier; and in goes various toxins from the damaged guts of such kids. We're talking encephalitis, ADEM, PPD-NOS - you name it.

Having come late to this thread, and having now read all the way through it, I'd like to make a couple of comments.

* I have come across at least 2 different references to studies (one by Haley et al) that showed that children with autism seemed to have a genetic predisposition - a 'polymorphism' - to low levels of glutathione. Thus they can't process heavy metals/toxins as well as other kids. Thus a combination genetic-environmental link.

* Carol Hoernlein of msgtruth.org has pointed out that the genes discovered in '07 with links to autism code for glutamate - "a major excitatory neurotransmitter":
www.medpagetoday.com/Neurology/Autism/tb/5082
Besides being an excitotoxin in its own right, glutamate/glutamic acid lowers glutathione levels. So kids with these genes should be kept free from glutamate, in their diet (& thus the value of the GF/CF diet, with wheat & dairy products high in glutamate), including aspartame (which breaks down into glutamate) - and in vaccines with live viruses, which have this substance in them (as a stabilizer). For example, the MMR. And so giving the MMR at the same time as other vaccines with heavy metals/toxins will tend to cause glutathione levels to be depleted; and if they already are low in a genetically susceptible child: a double whammy.

* The subject of schizophrenia has come up here. A recent article over here in the UK linked gluten with schizophrenia and type 1 diabetes. "Professor Ian Megson, head of the [genetics dept of the University of the Highlands and islands in Scotland] explained: 'the reason that gluten might provide a link between these apparently quite different diseases is that, in people with a particular genetic make-up that results in their bodies' inability to handle gluten in the normal way, the immune system becomes unusually active.'" But he/they could as easily be talking about glutamate, since not only is it in wheat products but it increases histamine response, thus making immune reactions worse. And what's more, lithium - a proven treatment for schizophrenia - it turns out, is a glutamate blocker.

The pieces are starting to come together. We're talking about both genetics and the environment. It's time we stopped the either/or debate, and got to the both/and; and started making headway, rather than just treading water, which is getting deeper as we speak.

Some people with schizophrenia benefit from GFCF diet and high dose vitamin B therapy. As far as I know, gene and brain issues have not been identified causing schizophrenia. Like autism, schizophrenia may very well involve other systems in the body in addition to the brain -- e.g. biochemistry and digestion. So, yeah, based on my limited knowledge -- maybe autism and schizophrenia have something in common -- but not necessarily in the way that Dave thinks.

As far as science requiring a narrower definition, it is important that autism be broken down into sub-groups. This is not done by large epidemiological studies that lump everyone with autism together and rule out any treatments or causation that don't apply to the majority. This could be done by studying individuals -- and, as mentioned previously, not only studying genes and the brain but also lab results, immune systems, health issues, digestion, etc.

As I said you are somewhere in a different land as far as autism research (and I noticed you failed to mention either mercury or thimerosal) ....and I had to read this a few times as it is so early...but..

" Science requires a narrower definition in order to advance." (narrower to identify then advanced to eliminate?,,)

"Secondly, it is a disorder with seemingly more in common with Schizophrenia (or homosexuality for that matter) in terms of etiology:"

Gotta stop you right there. The schizophrenia part as it compares with toxic exposure may have a commection (you are not worth my effort to cut and paste here) but the fact that you are placing homosexuality in the same sentence with "disorder" shows your skewed, genetic, bizarre thinking process thus places your quaint and disturbed theories here as null and void.

Many children with autism have had lab test results that show high levels of aluminum, mercury, copper and other metals, and a study by the California Department of Health Services found that "Air pollution [particularly metals and chlorinated solvents] boosts autism risk by 50 percent in newborns".[4] Based on these 2 findings, metal toxicity certainly seems to be involved in the development of autism.

A study by Dr. William Walsh found that only 4 out of the 503 autism-spectrum patients studied did not exhibit a serious metal-metabolism disorder.

And since you mentioned schizophrenia, consider this report of a patient who was misdiagnosed for 12 years as having paranoid schizophrenia and parkinsonism until they figured out he actually had Wilson's disease and it was the high copper levels that were causing his psychiatric problems. http://www.ncbi.nlm.nih.gov/pubmed/1353405

I do agree with this statement you made, "It would be a genetic combination which sets up a fetus for an environmental trigger which would somehow affect brain development, leading to the autistic phenotype."

However, where we would disagree is, I think the genetic susceptibility is some type of metal efflux disorder (due to the high levels of metals that children with autism have) or an immune deficiency (due to the symptoms of immune deficiency exhibited by many children with autism). Both of these genetic disorders could make children more susceptible to a vaccine injury.

And finally, I also disagree with this statement: "So far the data does not support the theory that it is due to a vaccine, or anything within a vaccine."

The Bailey Banks case found that the MMR vaccine did cause acute disseminated encephalitis which resulted in his developmental delay, and that this delay would not have occured with out the vaccine injury.

The Hannah Poling case declared that her autistic-like symptoms and seizures were triggered by vaccines.

Hardwired for autism? Surely humans who can not speak, do not have basic self-survival skills and lack social abilities are a fabulous evolutionary advance, right? I get a kick out of that one - "autism is advanced evolution."

This is inconsistent with the significant increase in autism over the past 25 years – from 1 in 10,000 to 1 in 150 at the CDC’s last count (8-year-olds in 2002) – and higher rates now reported in many school districts such as 1 in 100, and 1 in 60 reported in England. I imagine you will say that is due to better diagnosis, but that would be inconsistent with the UC Davis M.I.N.D. Institute’s recent study (see http://www.niehs.nih.gov/news/newsletter/2009/february/autism-rates.cfm )

This (hardwired brains) would also be inconsistent with the many reports of children responding to biomedical treatments addressing inflammation, oxidative stress, digestion, detoxification. I imagine you will say that none of these treatments is “proven” effective, which would be typical of the arrogance and lack of curiosity among so many in our medical establishment.

This would be inconsistent with the many reports of children regressing after reactions to the vaccines. Robert F. Kennedy jr. described the mothers who were telling these stories as, “And they were not hysterical people. They were scientists, they were doctors, they were psychiatrists, they were pharmacists, they were people that had their feet on the ground. They had attended the conferences, they had read the scientific literature, they had calmly and deliberately gone through this, and they had reached a conclusion.”

In an article in the April/May 2008 issue of Spectrum magazine RFK also said:

“In 2006, Kennedy wrote an article for Rolling Stone magazine called ‘Deadly Immunity’. The response to his piece was overwhelming: following the publication, Kennedy received thousands of letters and emails from all over the world. ‘The astounding thing was how alike all of them were and that people from Mississippi to New Delhi shared such identical experiences. Here is the typical scenario I heard: A mother took her toddler to the doctor where he received a spate of vaccines, became ill that night, often with a fever, sometimes with seizures, then lost the language he had, developed stereotyped behavior and regressed into a looking-glass world of debilitated relationships and social isolation. Essentially,’ Kennedy adds, ‘their lives were plunged into unimaginable agony.’ It seemed imperative to Kennedy to keep getting the story out to prevent the catastrophe from damaging other children.

”However, nothing prepared him for the resistance and anger he faced when discussing autism with politicians and the media. ‘The unbelievable thing is how these children’s stories are suppressed by the medical community, big Pharma and the American press. There is a total refusal to have the discussion and derision towards anyone who tries.’”

If the data isn't gathered, nothing will be "proven".

Your view of “hardwired” brains is also inconsistent with the growing body of research showing inflammation of the brain and dysregulation of the immune system among people with autism. Here is a list of studies posted at another site by someone who goes by the name of PassionlessDrone, who has more scientific background than me.

“Just during the past year, the following papers have been published concerning different immune responses in autism.

”Elevated immune response in the brain of autistic patients [Li / 2009] Additional evidence of an ongoing inflammatory response in the brains of children with autism.

”Increased IgG4 levels in children with autism disorder. [Enstrom / 2008] Increased IgG levels are identified in autism, but not in normal or children with developmental delays other than autism.

”Impact of innate immunity in a subset of children with autism spectrum disorders: a case control study [Jyonouchi / 2008] Different cytokine generation profiles in response to several types of stimulation are identified in autism versus normal controls, and among subsets of autism.

”Serum levels of P-selectin in men with high-functioning autism. [Iwata / 2008]. Decreased levels of a chemical with a role in inflammatory response are found in autism when compared to controls. As levels decrease, autism severity is found to increase.

”Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes [Ashwood / 2008]. More correlation between an factor involved with control of immune responses and autism severity.

”Altered gene expression and function of peripheral blood natural killer cells in children with autism [Enstrom / 2009]. Natural killer cells are found to be less numerous, and exhibit less cytotoxic capacities in children with autism.”

***

But I’m repeating myself. If you haven’t been influenced yet, Dave, you are not going to be influenced by this comment, so I am wasting my time, alas.

Teresa, I answered a great deal more than 1/3 of your questions. Personally, I believe autistic children's brains are hardwired for probable autism. Most likely don't even need any environmental trigger. And I don't believe pharmacological treatments are going to occur in our lifetimes (at least). I don't believe this will lead to specific therapies other than identification before symptom onset and even earlier behavioral interventions. Or, and I hesitate to mention this and certainly don't want to be crude, but I can't help but point out that the prevalence of Down syndrome is decreasing while the fetal incidence remains the same.

But don't worry, I doubt this will occur in autism for a few reasons. Firstly, this nonsense about a spectrum produces a heterogeneous population which can't be studied systemically (but has value when it comes time for lobbying and organizing and services). Science requires a narrower definition in order to advance. Secondly, it is a disorder with seemingly more in common with Schizophrenia (or homosexuality for that matter) in terms of etiology: polygenetic with these genes in various sinister combinations producing possibilities which nurture (beginning in the womb with maternal effects) actualizes. Not to mention molecular pathway misadventures (not even coded by genes).

Heterogeneity abounds. I think it is a condition with no single cause. There are thousands of possible environmental causes. So far the data does not support the theory that it is due to a vaccine, or anything within a vaccine. There is really no data to support the contention that these vaccines could cause a genetic aberration. Even to mention that points to a possible misunderstanding. It would be a genetic combination which sets up a fetus for an environmental trigger which would somehow affect brain development, leading to the autistic phenotype.

"But, I'm also really curious to know why some children are injured and others appear to be fine." said by CM

Equally, it would be incredibly helpful to find out why 95% who catch polio have mild symptoms and no paralysis. And of the other 5% most recover with no long-term problems. So is there a genetic weakness or an environmental problem connected with polio cases that result in paralysis?

Same question with measles: in healthy, well-nourished children over the age of two, measles rarely results in severe illness. Why do some children end up terribly sick? Is it genetic? Nutritional deficiencies? Inappropriate treatments?

I do believe that there is some genetic susceptibility, but ONLY a susceptibility.
Identical versus fraternal twin studies have shown that if one twin has autism, the other twin has a higher chance of having autism also. This risk is higher in identical twins than fraternal (which suggests a genetic susceptibility), BUT the rate of both identical twins having autism is not 100% (which proves that autism must also have an environmental component).

I also believe it's not solely genetic because you can't have a genetic epidemic.

But, I'm also really curious to know why some children are injured and others appear to be fine. Figuring out the answer to that question would be beneficial for many reasons such as:
1. If you know specifically how a vaccine triggered autism, it would be helpful for proving vaccine injury claims (such as the Hannah Poling case where she did have a genetic susceptibility).
2. Hopefully, if the susceptibility is identified it may provide clues to better treatment.
3. And if the susceptibility is known, then the children at risk could be protected

Also, I believe that autism has many different risk factors, and that it's not one single gene, and that it's very possible that some cases are 100% environmental. Some factors could be genetic metal efflux disorders (since so many children with autism have very high levels of toxic metals in their systems), genetic or acquired immune deficiencies (since so many children with autism battle chronic infections), mitochondrial disorders (because of Hannah Poling's case), or even certain viruses since viruses (such as Herpes Simplex 1) deplete important minerals like zinc (which is needed for metallothionein production and zinc has even been found to have a protective effect against the damage that aluminum causes to the blood brain barrier) etc.

One specific gene I think should be checked is ATP7B for all of the following reasons:
1. It's a metal efflux disorder that impairs mitochondrial function
2. It causes excessive storage of several metals (including mercury and aluminum which are both in childhood vaccines)
3. One out of every 90-100 people are believed to be a carrier of this gene. As carriers (meaning they have only one copy aka heterozygous), they are mostly asymptomatic. However, with some heterozygous diseases people are much more susceptible to certain environmental triggers.

However, this is still only a theory, and I don't think it's the only risk factor. I just suspect that it could be one of the many susceptibilities. But if they keep adding vaccines to the schedule, eventually, the amount of neurotoxins given will injure every child and susceptibilities won't matter.

Ben said, "The car crash analogy does not hold up because clearly most children who get vaccinated do not get autism."

Actually, if some stop lights were out of order not everyone passing through the intersection would have a car crash. Some would pass through safely. You could do genetic and brain studies to attempt to determine why some people proceeded with caution through the intersection and others did not, and why some people have better peripheral vision than others, and why some people have quicker reflexes than others (in addition to why some people heal from injuries better than others). But in the meantime someone better be focussed on making the streets as safe as possible.

I never said that autism has no genetic component. I never said that genetic research is a waste of time. But there is a dispropportionate amount of money spent on genetic research while other areas are underinvestigated.

When parents report their experiences with their children, we are constantly told things like, "The plural of anecdotes is not data!" The thousands of "anecdotes" of vaccine injury followed by autism should be the basis for research, instead of just being ignored and summarily dismissed.

I agree that it would be good to better understand genetic susceptibility to vaccine injury. Yet we must also develop a more sensible vaccine program for the sake of all kids, with better weighing of risks and benefits instead of so much dismissal/denial of the risks of vaccines.

And many geneticists say that it has been proven that vaccines do not cause autism. Many geneticists are looking only for direct gene-brain issues, not susceptibility to toxins or immune system problems.

And, the fact is, the more vaccines added to the schedule, the more children are affected. My neurotypical youngest daughter had a febrile seizure after receiving the MMR and the varicela vaccine at the same time. Fortunately, she recovered after a month of high fevers. Who knows what could have happened if she had received a flu shot containing thimerosal at the same time, or the DTaP? Then we would have said she has a genetic problem, yet without receiving as many vaccines at once as Hannah Poling she is o.k.

When 6 to 9 vaccines are given at once, kids who may otherwise have been completely healthy and normal are more likely to have serious adverse reactions.

My other two kids never had a febrile seizure. Is this because they are genetically different from my youngest, or because they never received the MMR and varicela vaccine at the same time? They came down with chicken pox before this vaccine existed. For many otherwise normal kids, the MMR plus varicela is too much for their little bodies to handle.

And, as Dr. Bernadine Healy has said, the injured children are not being studied. Parents whose children suffered vaccine reactions followed by autism are amazed that nobody from the medical or governmental agencies is interested in studying their children. Parents whose children recovered from autism with biomedical treatments are amazed that nobody from the medical or governmental agencies is interested in studying their children.

Instead we just keep hearing over and over, "Nobody knows what causes autism, and there is no cure, and any regression after vaccines is just a coincidence, and any improvement after medical treatment is just a coincidence, but a few million dollars were spent on a genetic study which found a certain genetic characteristic was more common among 1% of people with autism - aha!"

And we hear of large epidemiological studies which, as Dr. Healy also said, probably cannot tease out the multi-factorial and varied causes of autism.

The cavalier dismissal of parent's experiences is done in the name of scientific skepticism, but it is not skepticism -- it is prejudice, narrow-mindedness, and in some cases fear of admitting to problems among those who have vested interests.

"With family and twin studies showing some concordance" -- yes, only some concordance.

"Autism is a complex syndrome and it just makes sense to research it from every angle... It just makes sense that we should be trying to get as much information about children with autism as possible." Yes, that is exactly what many people in the biomedical camp are saying. Study the children. Study their immune systems, digestion, biochemistry, lab tests, vaccine histories. Look at everything, not only genes and the brain.

With family and twin studies showing ONLY some concordance, where do people get off claiming that autism HAS a genetic component?

The only unequivocal conclusion that can be drawn from the twin data is that environmental factors are significant, because monozygotic concordance is less than 100%. If you believe that any amount of concordance proves a genetic component causes autism, you simply don’t understand genetics. This is textbook stuff, hardly controversial. Take the higher rate of concordance between monozygotic (MZ) twins compared to dizygotic (DZ) twins – does that prove there is a genetic component? No. Several characteristics of both the prenatal and postnatal environment are more similar for MZ than DZ twins i.e. 75% of MZ, but less than 10% of DZ, twins share vascular connections in utero. Environmental interactions produce much higher concordance in MZ than DZ twins. For example, if a disorder requires an environmental trigger acting on multiple alleles, the environmental exposure leading to illness in one twin will lead to illness in the MZ co-twin, whereas a DZ co-twin will rarely inherit the entire ensemble of alleles. It’s the environment that causes the disorder AND the high rate of MZ concordance - the genes are merely templates being acted on by the environment: when an environmental trigger causes the variable expression of a genetic trait, you don’t blame the gene, you blame the environmental trigger. My previous example with red haired genes causing a bruising disorder is a clear cut example of high concordance that has nothing to do with genes and everything to do with the environmental trigger. My mumps example was also to the point: genes explain why humans and not monkeys get mumps, but if you want to know why humans get mumps at all, you better take a long hard look at the virus.

The “argument from incredulity” is simply not a valid argument: you don’t understand how concordance fails to prove a genetic component exists, therefore a genetic component must exist. I’m not even saying anything controversial here, this stuff is remedial genetics:

“”Autism does not follow a Mendelian pattern of inheritance, and in non-Mendelian disorders, environmental factors determine who becomes ill.””

With family and twin studies showing some concordance, where do people get off claiming that autism has no genetic component? Genes give us the rough outline, experience and environmental factors fill in the rest. As the adage goes, nature loads the gun and nurture pulls the trigger.

To twyla and others. I don't disagree that there should be other avenues of research funded but I have to disagree with you that genetic research is a waste of time. Autism is a complex syndrome and it just makes sense to research it from every angle. The car crash analogy does not hold up because clearly most children who get vaccinated do not get autism. This is a much stronger indication that there is some genetic predisposition to autism than your car crash analogy suggests. Furthermore successfully identifying a genetic predisposition to autism would benefit your camp greatly. I do not believe that vaccines cause autism, but for the sake of argument, if that were true and we could identify children at the most risk for autism, we could pre screen them and change the vaccine schedule for those children. It just makes sense that we should be trying to get as much information about children with autism as possible.

If you’ll indulge me, I’d like to tell you how I got into genetics work back in the early 80s. In 1983 my lab was the first to show that a certain childhood bruising disorder which caused discoloration of the skin was associated with the MC1R gene. A research team from Cornell discovered four alleles: Arg151Cys, Arg160Trp, Asp294His, and Arg142His, which were found to be the specific genotypes responsible for the phenotype that associated strongly with the bruising disorder. Epidemiologists from the National Institutes of Health were able to show that while 7% of people with these alleles had the bruising disorder, the disease occurred in only .1% of the rest of the population. That’s a 70-fold increase over the background rate and it’s a much more dramatic association than anything seen with autism so far. And yet, despite this remarkable level of concordance, the lack of inheritance pointed to some unknown environmental trigger that was also contributing to the disorder. It was also discovered that boys suffered from the disorder 10 times as frequently as girls and it was posited that testosterone somehow interacted with the gene product of the aberrant alleles to cause the disorder. While the government poured money into genetic research to look for a possible gene therapy treatment, a few poorly funded scientists decided to look for the environmental trigger. And they found it! As it turns out the kids with these four alleles acquired the bruising disorder when they went to school and got beat up by bullies. It was later learned that the four aberrant genes coded for the red hair phenotype, and despite the high association with the disorder, it turns out the environmental trigger (the bullies) were both the proximate and the ultimate cause. Girls were less affected because a lot of the bullies thought red hair was cute on girls. However it was not so easily tolerated on boys, thus they suffered a higher rate of bruising.

That story could have easily been true.

Genes have a tendency to seem important when you ignore the environmental causes of disease.

It's sort of like if there were a traffic intersection with broken stoplights where cars kept crashing into each other, and millions of dollars was spent on genetic research to determine why some people healed better from their injuries than others, but nobody thought of fixing the stoplights.

Only inherited disorders (e.g. hemophilia or sickle cell anemia) are phenotypes, they are present or absent based on the presence or absence of the gene (actually the gene product). Autism is not dependent on the presence or absence of any gene and that means that any genetic contribution to autism is neither sufficient nor necessary to produce the disease; autism requires environmental interaction with genes in order to manifest. And in that sense it's pointless to talk about genes as contributing factors. Is it easier to make children genetically less susceptible to heavy metal poisoning or is it easier to stop poisoning them with heavy metals. All the research is going into the pointless pursuit of the former strategy.

If a gene were present or absent in all cases of autism, my three year old would be able to find it. The most that can be hoped for genetically are predispositions which are minnows if they exist at all. The real effect is to have all of us stare real hard for the minnows so that we miss the whale docked to the other side of the boat. So yes it can be harmful to look for very small pieces to the puzzle, there are only so many of us looking and it just makes more sense to put those huge border pieces together instead of looking for tiny pieces which may not even be there.

There was in fact one very important gene study published earlier this year, Campbell et al, 'Distinct Genetic Risk Based on Association of MET in Families With Co-occurring Autism and Gastrointestinal Conditions':

CONCLUSION. These results suggest that disrupted MET signaling may contribute to increased risk for autism spectrum disorder that includes familial gastrointestinal dysfunction.

1. You can't blame scientists for headlines and the media hype. They have little to no control over such matters. Furthermore, the difference between the science and the media spin is vast. These are two different things.
2. So if a genetic find affects <1% of a phenotype (in this case autism), then it could be very significant if it points toward a molecular pathway shared by many in the phenotype. Having genes which entail Alzheimer's disease by 50 affects only a few familes, but because every gene identified has something to do with amyloid, it support the current hypothesis that amyloid causes autism.

That story didn't work out so well with ALS and superoxide dysmutase mutantions. It will also likely not work out very well with autism because the definition of "spectrum" entails a hetereogeneous disease. But just because it is complex and difficult is no reason at all to give up. Everyone (without a preconceived notion they feel has to be True) should welcome any advance in medicine.

The Human Genome Project does not think multigene disorders are candidates for gene therapy.

If genetic research may benefit @ 1% of the autism population, perhaps genetics should receive @ 1% of Federal and Autism Speaks' research funding.

Kevin

"Multigene disorders - Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy.

Unfortunately, some the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes, are caused by the combined effects of variations in many
genes. Multigene or multifactorial disorders such as these would be especially difficult to treat effectively using gene therapy."

The selection of desired heritable characteristics in order to improve future generations, typically in reference to humans. The term eugenics was coined in 1883 by the British explorer and natural scientist Francis Galton, who, influenced by Charles Darwin’s theory of natural selection, advocated a system that would allow “the more suitable races or strains of blood a better chance of prevailing speedily over the less suitable.” Social Darwinism, the popular theory in the late 19th century that life for humans in society was ruled by “survival of the fittest,” helped advance eugenics into serious scientific study in the early 1900s. By World War I, many scientific authorities and political leaders supported eugenics. However, it ultimately failed as a science in the 1930s and ’40s, when the assumptions of eugenicists became heavily criticized and the Nazis used eugenics to support the extermination of entire races.

""I don't understand why a genetic component to autism is such anathema to the patrons of this website.""

Probably for the same reason a unicorn component is anathema. It's a waste of resources that could be better used focusing on the real causes of autism. So what if they ever do find a unicorn component that associates with a small percentage of autistic children. They haven't even proven the unicorn component exists but they've proven it will be of little to no value in treating and/or preventing autism. Money and resources are finite, our children's time on this Earth is finite. Any amount of waste is unacceptable.

It is very easy to associate a gene with a disease even if the gene plays no part whatsoever in the disease. Why do humans get mumps and not monkeys? The answer is 100% genetic (the 2% difference between human genes and their nearest primate relatives), and yet our genes tell us nothing about why we humans get mumps. For that you have to look at environmental factors, in this case, a virus.

Yesterday's L.A. Times had an article called "Researchers find common DNA variations in people with autism" regurgitating all of the baloney that Mark addresses above. One of the conclusions of the article was:

"Up to now, the medical community could say very little about what causes autism or how to treat it. The lack of scientific knowledge about autism has led to a proliferation of pseudoscientific explanations for the disorder, as well as unproven treatments."

Should you feel inspired to write to the author, the email address is ttsouderos@tribune.com. Perhaps some of you could tell your stories of your children's recovery with "unproven treatments".

One of the frustrating things about those focussed on autism genetics is that the discovery of an apparent genetic aberation is accompanied by a dismissal of biomedical causation and treatments for autism. Even if the discovery holds up, it could very well relate to to mitochondrial disorder, low glutathione, tendency towards allergy and auto-immunity and inflammation etc. resulting in susceptibility to harm from mercury, aluminum, injection of multiple viruses etc.

Do we live in a parallel universe? Thank goodness for a few voices such as Dr. Healy.

All of the news articles I am seeing indicate that the allele in question is present in 65% of children with autism, as opposed to 35%. It drives me crazy that it's so hard to get ahold of papers published in Nature.

Mark - Can you post something from the papers in regards to the 35% incidence in the autism population? The 65% value is very widely distributed everywhere but this site.

Hej.
I discovered this webpage. Great one.
I am a physician with experience with autistic children screening in a normal population and off course one off my 3 children has it all...
I found on just simple looking and asking:
-lymfeglands in the cervical region.....
-teeth ektopic, double and to many in crowded mandibula or maxilla
-hipproblems
-off course ADHD/ADD,tics, Tourette syndrome symptoms
-One of the KPR(Knee Tender reflexes) down or lower
-chryptorchism, phimosis, urehral valves
-boys with a lot off healthy looking hair
-tibiarotation in the knee

May be of any help and yes off course flagelates in vinylfloors on the bedrooms of the children according to swedish research

Adriana, very interesting about the monkeys. They could have been part of vaccine or viral (possibly HIV??) experiments for all we know! This type of research goes on all the time, clues for autism in front of their eyes. Crying shame.

- 67% of 170 respondents said that injected methyl B12 helped their kids, and

- 74% of 803 respondents said that detox (chelation) helped their kids, and

- 58% of 1,502 respondents said that digestive enzymes helped their kids.

Yet in addition to being constantly told that parental perceptions are worthless, we are also told that if something doesn't work for everyone, it's not a legitimate treatment, and any apparent improvement is just the placebo effect, or would have happened without the treatment due to the passage of time. The biological diversity of autism is ignored, and if some people do not benefit from a treatment for whatever reason this is looked at as proof that the treatment is not effective.

And, if some people become autistic without vaccines and others get vaccinated without becoming autistic, this is pointed to as proof that vaccines do not cause autism.

Yet when a genetic study states that a statistical link, however small, has been found between a genetic aberation and autism, this is trumpeted with headlines that a genetic basis has been found for autism, even if many people without autism have that genetic aberation and many people with autism do not.

Why do these studies get a free pass from the following statments that are always said to parents who witnessed vaccine injury and/or improvement from biomedical treatments:

Huge amounts of money spent on the search for genes, and ignoring of so much evidence right in front of us that deserves further investigation.

Thanks for the excellent analysis, Mark.

Adriana, that's a very interesting comment.

Kim, as always, perfect picture!

Since Dr. Offit is an infectious disease specialist, if he wants to study autism he should get involved in an area related to his education and experience: the role of vaccines and antibiotics in causing viral, yeast, and bacterial infections among people with autism. He could also study kids who have recovered from autism when these infections were treated, such as Stan Kurtz's son.

Mark, thank you for your excellent analysis of genetic research papers, and for all who have commented on how irrelevant the gene hunt is to solving the disaster of autism for families and society. The "common pathway" must be looked for in the brain - and if it is the amygdala, how disruption of maturation affects this particular area. I will persist in trying to point out the vulnerability of the auditory system to toxic and anoxic damage, and its importance for learning to speak.

Laura, same here. I had contacts and battled eye infections and redness/pain for years. I thought I was too young to handle the contacts well - nope. I (insert eye roll here) am the rare human who is allergic to putting mercury into my body willfully. Or in the case of vaccines, unwillfully.

Thank you, Mark. That was worth every minute of the 135 minutes that it took to read this article. The immaculate mutation-- wonderful. I guess you could say that all they've found so far is not even a hot spot in a dixie cup.

I had just had some of this explained to me by someone in the movement last week when I was asking about neurexins and neuroligins in autism and the work of genes researcher, Eric Kandel. I have to admit that I still don't understand it all, but what interested me the most in the studies of neuroligins and autism was the fact that the researchers, while claiming to be chasing an "immaculate" de novo mutation which suppressed neuroligins in the amygdala and supposedly caused autistic behavior, were *using an environmental factor to induce this effect in animals*. Kandel used a virus: http://sfari.org/people/EricRKandel (check out the Simons Foundation and SFARI board-- Fombonne). Also, si-RNA can be used in the lab to suppress neuroligin expression and it might be of interest that synthetic "small-interfering RNA" is being investigated for use in vaccines.

So here these genes researchers are actually *proving* that autistic behavior in animals can be caused environmentally, but this is not what they report. Instead they describe some straw they're grasping at but have not actually found.

These experiments of inducing autistic behavior in animals must be very common: our ABA therapist describes her university as having "inherited" a huge population of "autistic monkeys" from somewhere. Maybe from Cold Spring Harbor or some place similar. I'm going to assume that researchers rate of success in environmentally inducing autistic-like behaviors in animals is close to 100%. What would the "P" value of that be? Better than .5%?

Kandel had previously spent his time trying to prove (unsuccessfully) the genetics of schizophrenia. Jonathan Leo-- the neuroanatomist recently in the news for being threatened by JAMA editors-- wrote a critique of Kandel's work: http://tinyurl.com/c8d7mt

Studies are being conducted in order to evaluate the effects of mercury vapor on gene expression in rat brain. Mercury constitutes 50% of dental amalgam, and amalgam restorations release small amounts of mercury vapor (elemental mercury). This vapor is absorbed and distributed throughout the body, localizing in the kidney and brain. Dental practitioners who use mercury have elevated urinary mercury levels, and in persons who have amalgam restorations, the number of amalgams is directly proportional to the urinary mercury concentration. Since mercury is a known neurotoxicant, exposure to mercury vapor during pregnancy may interfere with brain development. In contrast to animal studies, reports of human reproductive and developmental effects due to occupational vapor exposure have been inconclusive.

Since controlled mercury vapor (the form of mercury that is of concern) exposures require an inhalation facility with analytical capability and safety controls, initial series of experiments will be conducted using methyl mercury (MeHg). Like mercury vapor MeHg is lipophilic, and mercury levels can be easily elevated in brains of rats injected with MeHg. Progress to date has focused on dissecting rat brain into six regions, including targets for mercury (cerebellum, cortex, and hippocampus). Immunoblotting experiments with heat shock protein (hsp) antibodies are planned in order to identify region-specific induction of hsps, as well as radiolabeling studies to asses de novo synthesis and immunohistochemistry to identify cell-specific induction. Future mercury vapor inhalation studies in rats are being coordinated through the NIEHS Inhalation Toxicology Group, RTP, NC.

These studies will help in identifying the responses of target tissues to low-level mercury exposures. This will equip the PHS to better assess the risks associated with exposures to mercury from amalgam restorations. [PreME, PostMS]

At 16 years old, shortly after I began wearing contact lenses in 1976, I can remember the optometrist telling me that I must be allergic to the thimerosol in the saline solution he recommended I use. He explained that thimerosol was used as a preservative and had me change brands to one which was thimerosol free. Instantly, no more eye redness and I have successfully worn contacts now for over 30 years. Fast forward to my newborn identical twins' vaccines in 1995, and both are in the spectrum, one more so than the other. Little did I know that all their many vaccines contained thimerosol! Coincidence? I think not! Could they be allergic to thimerosol too, only in a much more severe way, because the mercury-based preservative entered their bloodstreams at a critical point in their development? Why can't a study be designed to look at a genetic based theory of inheriting a hypersensitivity to mercury?

Mr. Blaxill,
I have heard you speak and value your intelligence and untiring efforts to find the true answers to this epidemic. I am hearing about the swine flu and the fears of it spreading. Gee, where is the media coverage of the autism epidemic that is real and it is happening now to our children? I am starting to wonder if any children born today are healthy. I doubt it is simply the vaccines. There must be another piece to the puzzle. Look at the chemical that disarms the liver. Is that the key to the lock? Is it damage to the liver by a chemical that allows the neurotoxic vaccines to cause harm to these little brains? There is so much that needs to be studied and it seems research is not looking in the right direction. The parents' conviction that vaccines are linked to the onset of symptoms is probably the most valuable information known. Thank you for your efforts.

Thank you, Mark, for sifting through this research.
When a geneticist told me that my son had PTEN, BRRS, that it was a genetic deletion inherited from either my husband or from me, I knew that they would not find this when they tested both of us. I was tritely told that PTEN was the cause of his autism.
My question was never answered that since the PTEN was not inherited, could this mutation/deletion have taken place as a result of vaccines. I was patted on the head more or less and dismissed as foolish.

My burning question: could the flu shot I had while pregnant (something I have never had during any other pregnancy) have caused this de novo mutation? or, and this is the part that I need explained, could the mutation happen after birth as a result of my son's vaccines?
Thank you to anyone who can answer this for me.

I was going to skip commenting on your post but I have got to ask how you think pointing out a <1% "genetic risk" compared to all the hype and headlines this kind of research garnishes ( plus time, money ,and misinforming the Public )is "fallacious"?

Even if a gene aberration were in fact the cause of a tiny fraction of autism cases (which has not been remotely proven), all the rest of the multitude of autism cases are de facto NOT caused by the gene aberration (because the rest of autistic kids don't have the aberrant gene!).

And that means that...

Even if some therapy were developed that helped that tiny fraction of autistic kids with the gene aberration, it could not possibly help other autistic children. The limit of potential successful therapies for a corrupted gene is limited by the gene product. If the gene is aberrant it's not producing the proper protein. The only therapy that could help would be to find a way to get rid of the bad protein and/or add in the good protein. Every possible successful strategy has to involve doing one or both of those things. But all the other autistic kids already have the good protein and none of the bad protein; the therapy can not do anything for them.

After the 1972 mercury poisoning in Iraq, there was widespread concern over the
use of mercury fungicides in seed dressing. The ethyl mercury fungicide Ceresan
M, claimed to be responsible for the two earlier outbreaks of poisoning in 1956
and 1960 in Iraq, was tested in Drosophila to study its mutagenic
potentialities. Of the two concentrations used, namely 30 and 40 mg of the
chemical in 100 cc of the food medium, the latter treatment resulted in a
significant increase in the frequency of sex-linked recessive lethals.

Lead and mercury are toxic metals that are widely distributed in the
atmosphere, soil, and groundwater. It is estimated that 2-4 x 10(4) tons of
these metals are released annually into the environment by natural and
industrial processes. Therefore, human exposure to low relatively nontoxic
concentrations of these metals is unavoidable. However, the possible health
effects of such exposure remain controversial. We have previously reported that
low, subthreshold concentrations (0.1-1 microM) of these metals are mutagenic
in the transgenic Chinese hamster ovary cell line AS52. The purpose of the
present study is to determine the types of MUTATIONS INDUCED IN THE GPT GENE in AS52 cells. Using multiplex polymerase chain reaction and southern blot
analyses, we characterized the 138 lead-induced, 192 mercury-induced, 29
reactive oxygen radical-induced, and 20 spontaneously arising mutants for point
and deletion mutations in the gpt gene. Similar levels of point mutations were
observed in the lead- and mercury-induced populations (47.8 and 53.6,
respectively), which was significantly less than that occurring in the
spontaneously arising and reactive oxygen intermediate-induced mutants.
However, further examination of the data revealed that at concentrations of the
metals of equal to or less than 0.4 microM, the majority of the mutations in
the gpt gene were point mutations, while at higher concentrations, DELETIONS(partial and complete) WERE THE PROMINENT TYPE OF MUTATION.*** These results are consistent with the hypothesis that lead and mercury induce mutations in
eukaryotic cells by at least two distinct mechanisms.

You display fallacous thought here. Just because the finding affects a small percent of autistic children does not entail insignificance. Perhaps it, or a like finding, will open up larger therapies in the future.

All according to plan, the CDC and FDA release this information to the general public that "AUTISM is GENETIC" right when this Swine Flu is becoming larger so that the people will give into the mass media and fight against our cause.

In return, the media will strike against us and make us look like we are the ones feeding this mass outbreak because we are refusing to vaccinate our children with the new "Swine Flu" shot. People get ready! Get ready to falsify documents if necessary.

The media will use the CDC's information that Autism is Genetic and that to refuse the shot for the "Swine Flu" is Anti-American. Look up "Executive Order 13295" and there you will find your information. This is no lie.

I'm curious. So when my son regressed into autism, a gene triggered him and hundreds of thousands of other children when they got vaccines? If my cadherin 10 and cadherin 9 genes are mutated then where are the other autistic off-spring in my family tree?

I spent the $4,200 to look at my son's genetic makeup and the only abnormality we found was a C677T mutation in the methylenetetrahydrofolate reductase (MTHFR).

God help us if this is the kind of propaganda that is clearing the trail for the government's program of the harvesting of DNA at birth.

Mark,
Thank you for this excellent review. I had just finished reading Bloomberg's article "Autistic Kids Have Altered Genes Controlling Brain Development" and suggested to the author that the misleading headline be corrected. The article itself contained enough information to demonstrate that the headline was not warranted.

If they can find a gene that exists in people with autism that is not found in the general population then some progress may be recognizable, but it doesn't sound like that has happened yet.

Personally, I think it is a futile and unwise effort, and anyone who has ever worked with computer code should know this intuitively. I would like to see these same researchers compare a couple code versions, and predict the outcome of changes...without knowing the language the code was written in. Its just that laughable. The necessary "beta testing" of any gene derived therapy on humans (fetuses?), if they ever got that far, would be far more of a moral hazard than the chelation study that was aborted.

An environment first approach is a matter of getting back to basics. Its low tech and in many cases low cost, which is probably why there is no commercial scientific interest in it.

“These examples highlight a different paradigm for the genetic basis of autism. Rather than being an inherited disease, autism may be the result of many independent loci that rarely delete or duplicate during gamete [sperm or egg] production.”

It amazes me that nowhere do they find an example that will fully illustrate this false hypothesis. Yet they can't seem to let go of this, hanging onto it like a lifeline. Keep hanging on I say, it just may save your lives!

There is such dishonesty from the genetics research. Of course their incomes depend on minimizing the environmental connection.

As more research was published on the SV40 viral contamination of the oral polio vaccine about 10 years ago, most articles and authors stressed that it took the combination of genetic risk, for a particular cancer, PLUS exposure to the SV40 virus to produce human cancer in a particular individual. Genetic risk "without" environmental, (SV40)exposure, would not be enough to produce a mesothelioma. In retrospect those articles seem quite objective by today's standards and fanfare surrounding autism genetic publications.

Everyone knows there are immediate health dividends when you clean up the environment like in the case of tetra-ethyl lead. Look at the industries that tried to keep that toxin in our environment. Why weren't they pushing the gene's on the damage lead was doing. Well, because there's wasn't a genetics industry. Now real money can be made doing genetic research and we can ignore the more difficult problem of cleaning up our environment and the requisite political will to make it so.

Oh, great, I guess the next step for them will be to announce that yes autism is genetic... but we just have to find the right combination of genes! Just give us a century or two. For the number of possible combinations is, of course, infinite. Thus allowing themselves infinite number of centuries to identify the right combinations of genes, and infinite number of research dollars in their pockets. Infinite number of jobs for life. Infinite number of opportunities to spread the combination gene theory in the media. While the number of damaged kids continues to spiral to infinity.

Imagine the cognitive dissonance that Offit must be feeling on a daily basis. It's so great that he feels compelled to direct that cash not to his own research on vaccines, but to someone else's genetic research attempting to prove that his own research on vaccines doesn't hurt people. What a waste. Hint to Offit: If you really want the glory of proving what causes autism once and for all, you're going to have to start by looking in the mirror.

Thank you very much for this comprehensive assessment of the research. I am very appreciate! L-Glutamine, which "helps the body with glutathione metabolism, and could affect detoxification capacity," has been one of the only treatments that helped my son with his weakened immunological skin rashes, so I place my bet on that research. If it happens to be true that, "“Individuals with comparatively weak physical connectivity between neurons will be most vulnerable to environmental factors,” why not give suspectible children methylphenidate (ritalin) before vaccinating.

Thank you for reading these studies for me so I DON'T HAVE TO! Cause I don't have time (see AoA essay from "Any Mom, Any Dad") and don't trust anything from CHOP anyway. At least we have you, someone trustworthy, we can depend on to weed through the crap out there.

Let's all get real...this is a way to desuade our thinking that this was genetic all along. I don't bash the genetic, but I bash it if it doesn't follow through to certain conclusions...that is, what interacts with that gene, is is too much iron in the body (hemochromatosis), does it interact with mercury or the lack of methylation or metallothionein or glutathione, does it interact with immune function, how neural networks are laid down or eastily destroyed or disrupted, is it interacting with toxins of any kind, or an infection in utero. Does it damage mitochondria and cell function? Come on scientist, you can't pull the wool over my eyes...they are, or the genes you found, are the things I just pointed out, which goes back to, what is causing mutations?

My friend Jim told you in post back...he is finding chemo drugs in our waters, and this is a known mutagen. So is mercury. So is lead and aluminum. So can fluoride. So can MSG. PLUEEZ...the man behind the curtain is not fooling me who the Great OZ is. The Great and terrible OZ, is someone who doesn't want to admit they have poisoned this generation of children, mutated our genes from parental vaccine series, and have caused unbeknownst mutagenic affects in our polluted world. Frogs get three legs from dioxins? Is that genetic? It happened in utero?